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Diabetes 53:2443-2448, 2004
© 2004 by the American Diabetes Association, Inc.

Leptin Stimulates Ischemia-Induced Retinal Neovascularization

Possible Role of Vascular Endothelial Growth Factor Expressed in Retinal Endothelial Cells

Eri Suganami1,2, Hitoshi Takagi1, Hirokazu Ohashi1, Kiyoshi Suzuma1, Izumi Suzuma1, Hideyasu Oh1, Daisuke Watanabe1, Tomonari Ojima1, Takayoshi Suganami2, Yasushi Fujio3, Kazuwa Nakao4, Yoshihiro Ogawa2,5, and Nagahisa Yoshimura1

1 Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
2 Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan
3 Department of Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
4 Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
5 Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan

Diabetic retinopathy is the leading cause of new blindness in adults in developed countries. Leptin, an adipocyte-derived hormone, stimulates endothelial proliferation and angiogenesis. This study was designed to elucidate the pathophysiologic role of leptin in the progression of retinal neovascularization. Using the retinopathy of prematurity model, a mouse model of ischemia-induced retinal neovascularization, we have demonstrated more pronounced retinal neovascularization in 17-day-old transgenic mice overexpressing leptin than in age-matched wild-type littermates. Ischemia-induced retinal neovascularization was markedly suppressed in 17-day-old leptin-deficient ob/ob mice. Western blot analysis revealed that a biologically active leptin receptor isoform is expressed in mouse retinal endothelial cells. Leptin receptor expression was also detected in primary cultures of porcine retinal endothelial cells, where it upregulated vascular endothelial growth factor (VEGF) mRNA expression. This effect was thought to be mediated at least partly through the activation of signal transducers and activators of transcription (STAT)3, because adenoviral transfection of the dominant-negative form of STAT3 abolished the leptin-induced upregulation of VEGF mRNA expression in retinal endothelial cells. This study provides evidence that leptin stimulates the ischemia-induced retinal neovasucularization possibly through the upregulation of endothelial VEGF, thereby suggesting that leptin antagonism may offer a novel therapeutic strategy to prevent or treat diabetic retinopathy.

Address correspondence and reprint requests to Hitoshi Takagi, MD, PhD, Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: hitoshi{at}kuhp.kyoto-u.ac.jp


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.